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1.
PLoS Pathog ; 20(8): e1012144, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39172739

RESUMEN

Several reports suggest that intestinal tissue may be a natural niche for Chlamydia trachomatis infection and a reservoir for persistent infections in the human body. Due to the human specificity of the pathogen and the lack of suitable host models, there is limited knowledge on this topic. In our study, we modelled the course of the chlamydial infection in human primary gastrointestinal (GI) epithelial cells originating from patient-derived organoids. We show that GI cells are resistant to apical infection and C. trachomatis needs access to the basolateral membrane to establish an infection. Transmission electron microscopy analysis reveals the presence of both normal as well as aberrant chlamydial developmental forms in the infected cells, suggesting a possible cell-type specific nature of the infection. Furthermore, we show that the plasmid-encoded Pgp3 is an important virulence factor for the infection of human GI cells. This is the first report of C. trachomatis infection in human primary intestinal epithelial cells supporting a possible niche for chlamydial infection in the human intestinal tissue.


Asunto(s)
Infecciones por Chlamydia , Chlamydia trachomatis , Organoides , Humanos , Chlamydia trachomatis/fisiología , Organoides/microbiología , Organoides/patología , Infecciones por Chlamydia/microbiología , Mucosa Intestinal/microbiología , Células Epiteliales/microbiología , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas
2.
Nat Rev Microbiol ; 21(7): 448-462, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36788308

RESUMEN

In recent years, substantial progress has been made in the understanding of the intracellular lifestyle of Chlamydia trachomatis and how the bacteria establish themselves in the human host. As an obligate intracellular pathogenic bacterium with a strongly reduced coding capacity, C. trachomatis depends on the provision of nutrients from the host cell. In this Review, we summarize the current understanding of how C. trachomatis establishes its intracellular replication niche, how its metabolism functions in the host cell, how it can defend itself against the cell autonomous and innate immune response and how it overcomes adverse situations through the transition to a persistent state. In particular, we focus on those processes for which a mechanistic understanding has been achieved.


Asunto(s)
Infecciones por Chlamydia , Chlamydia trachomatis , Humanos , Chlamydia trachomatis/metabolismo , Inmunidad Innata , Interacciones Huésped-Patógeno , Infecciones por Chlamydia/microbiología
3.
Elife ; 112022 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-36155135

RESUMEN

Chlamydia trachomatis (Ctr) can persist over extended times within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma (IFN-γ) released by immune cells as a mechanism of immune defence. IFN-γ activates the catabolic depletion of L-tryptophan (Trp) via indoleamine-2,3-dioxygenase (IDO), resulting in persistent Ctr. Here, we show that IFN-γ induces the downregulation of c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued Ctr from IFN-γ-induced persistence in cell lines and human fallopian tube organoids. Trp concentrations control c-Myc levels most likely via the PI3K-GSK3ß axis. Unbiased metabolic analysis revealed that Ctr infection reprograms the host cell tricarboxylic acid (TCA) cycle to support pyrimidine biosynthesis. Addition of TCA cycle intermediates or pyrimidine/purine nucleosides to infected cells rescued Ctr from IFN-γ-induced persistence. Thus, our results challenge the longstanding hypothesis of Trp depletion through IDO as the major mechanism of IFN-γ-induced metabolic immune defence and significantly extends the understanding of the role of IFN-γ as a broad modulator of host cell metabolism.


Asunto(s)
Chlamydia trachomatis , Interferón gamma , Proteínas Proto-Oncogénicas c-myc , Línea Celular , Chlamydia trachomatis/fisiología , Femenino , Glucógeno Sintasa Quinasa 3 beta , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón gamma/metabolismo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Nucleósidos de Purina , Pirimidinas , Ácidos Tricarboxílicos , Triptófano/metabolismo
4.
PLoS Pathog ; 17(9): e1009874, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34473800

RESUMEN

Staphylococcus aureus is a major human pathogen, which can invade and survive in non-professional and professional phagocytes. Uptake by host cells is thought to contribute to pathogenicity and persistence of the bacterium. Upon internalization by epithelial cells, cytotoxic S. aureus strains can escape from the phagosome, replicate in the cytosol and induce host cell death. Here, we identified a staphylococcal cysteine protease to induce cell death after translocation of intracellular S. aureus into the host cell cytoplasm. We demonstrated that loss of staphopain A function leads to delayed onset of host cell death and prolonged intracellular replication of S. aureus in epithelial cells. Overexpression of staphopain A in a non-cytotoxic strain facilitated intracellular killing of the host cell even in the absence of detectable intracellular replication. Moreover, staphopain A contributed to efficient colonization of the lung in a mouse pneumonia model. In phagocytic cells, where intracellular S. aureus is exclusively localized in the phagosome, staphopain A did not contribute to cytotoxicity. Our study suggests that staphopain A is utilized by S. aureus to exit the epithelial host cell and thus contributes to tissue destruction and dissemination of infection.


Asunto(s)
Cisteína Endopeptidasas/metabolismo , Células Epiteliales/patología , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Animales , Muerte Celular/fisiología , Células Epiteliales/microbiología , Humanos , Ratones , Staphylococcus aureus/patogenicidad , Factores de Virulencia/metabolismo
5.
mBio ; 11(6)2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33323513

RESUMEN

The opportunistic human pathogen Staphylococcus aureus causes serious infectious diseases that range from superficial skin and soft tissue infections to necrotizing pneumonia and sepsis. While classically regarded as an extracellular pathogen, S. aureus is able to invade and survive within human cells. Host cell exit is associated with cell death, tissue destruction, and the spread of infection. The exact molecular mechanism employed by S. aureus to escape the host cell is still unclear. In this study, we performed a genome-wide small hairpin RNA (shRNA) screen and identified the calcium signaling pathway as being involved in intracellular infection. S. aureus induced a massive cytosolic Ca2+ increase in epithelial host cells after invasion and intracellular replication of the pathogen. This was paralleled by a decrease in endoplasmic reticulum Ca2+ concentration. Additionally, calcium ions from the extracellular space contributed to the cytosolic Ca2+ increase. As a consequence, we observed that the cytoplasmic Ca2+ rise led to an increase in mitochondrial Ca2+ concentration, the activation of calpains and caspases, and eventually to cell lysis of S. aureus-infected cells. Our study therefore suggests that intracellular S. aureus disturbs the host cell Ca2+ homeostasis and induces cytoplasmic Ca2+ overload, which results in both apoptotic and necrotic cell death in parallel or succession.IMPORTANCE Despite being regarded as an extracellular bacterium, the pathogen Staphylococcus aureus can invade and survive within human cells. The intracellular niche is considered a hideout from the host immune system and antibiotic treatment and allows bacterial proliferation. Subsequently, the intracellular bacterium induces host cell death, which may facilitate the spread of infection and tissue destruction. So far, host cell factors exploited by intracellular S. aureus to promote cell death are only poorly characterized. We performed a genome-wide screen and found the calcium signaling pathway to play a role in S. aureus invasion and cytotoxicity. The intracellular bacterium induces a cytoplasmic and mitochondrial Ca2+ overload, which results in host cell death. Thus, this study first showed how an intracellular bacterium perturbs the host cell Ca2+ homeostasis.


Asunto(s)
Calcio/metabolismo , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/fisiopatología , Staphylococcus aureus/fisiología , Apoptosis , Muerte Celular , Citoplasma/metabolismo , Retículo Endoplásmico/metabolismo , Células HeLa , Homeostasis , Interacciones Huésped-Patógeno , Humanos , Viabilidad Microbiana , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo
6.
Int J Med Microbiol ; 308(6): 607-624, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29217333

RESUMEN

Staphylococcus aureus is a notorious opportunistic pathogen causing a plethora of diseases. Recent research established that once phagocytosed by neutrophils and macrophages, a certain percentage of S. aureus is able to survive within these phagocytes which thereby even may contribute to dissemination of the pathogen. S. aureus further induces its uptake by otherwise non-phagocytic cells and the ensuing intracellular cytotoxicity is suggested to lead to tissue destruction, whereas bacterial persistence within cells is thought to lead to immune evasion and chronicity of infections. We here review recent work on the S. aureus host pathogen interactions with a focus on the intracellular survival of the pathogen.


Asunto(s)
Citoplasma/microbiología , Interacciones Huésped-Patógeno , Fagosomas/microbiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/patogenicidad , Animales , Autofagia , Humanos , Evasión Inmune , Macrófagos/microbiología , Ratones , Fagocitos/microbiología , Fagocitosis , Staphylococcus aureus/genética
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